This invention relates to an improved process involving decarboxylation. Specifically, it involves the preparation of Zomepirac and analogs via acidic decarboxylation.
Decarboxylation via heterolytic cleavages generally fall into two catalogues:
I. Decarboxylation of acids whose anions are less stable with respect to decarboxylation than the unionized acid; and
II. Decarboxylation of acids whose unionized form is more susceptible to decarboxylation than their anions.
For most acids, decarboxylation (Catalogue I) takes place in a basic medium, i.e., in their anion forms. However, for .alpha. or .beta.-keto acids, decarboxylation (Catalogue II) usually undergoes much easier in an acidic medium, i.e., in their unionized free acid forms. The keto acids' exceptional preference for acidic decarboxylation is attributed to the following mechanism: ##STR1## Zomepirac and its analogs are useful anti-inflammatory agents of the structural formula (I). ##STR2## These compounds have been previously prepared in four steps by decarboxylation of a diester, (II). ##STR3##
It has been known that heterocyclic acids of similar structural features, for example, pyridine-3-carboxylic acid and thiazole-4-carboxylic acid, decarboxylate more rapidly in basic media than in acid solvents (Patai, The Chemistry of Carboxylic Acids and Esters, Interscience, N.Y., 1969, pg. 602).
The prior art decarboxylation as described above is usually conducted in an organic base such as quinoline or neat at relatively high temperatures. To preserve selectivity of decarboxylation, protection of the acetic acid is required under the drastic conditions. Accordingly, two extra steps, i.e.,
(a) the preparation of the monoester (III); and PA1 (b) the hydrolysis of ester (IV) to afford (I) are added to the process making it a 4-step process. PA1 Acetic acid PA1 Chloroacetic acid PA1 Chlorodifluoroacetic acid PA1 Dichloroacetic acid PA1 Difluoroacetic acid PA1 Trichloroacetic acid PA1 Pentafluoropropanoic acid PA1 Trifluoroacetic acid PA1 Toluene PA1 Benzene PA1 Xylene PA1 Tetrahydrofuran PA1 1,2-Dimethoxy-ethane PA1 Dioxane
As expected, the overall yields of the prior art process are generally lower due to the additional steps and the more drastic conditions of the decarboxylation.
To the contrary, the present process relates to a single-step acidic decarboxylation by which pyrrole acetic acids of formula (I) are unexpectedly prepared from diacid (IIa) under mild conditions: ##STR4## As shown above, the tedious blocking and deblocking steps are eliminated, and the drastic decarboxylation condition is avoided. Both contribute to the excellent yield of compound (I) (90-95%).